Despite a long tradition of study in mammals, important questions remain regarding the genetic and developmental basis of differences in tooth shape. Here, I propose a novel approach to the study of tooth shape. I concentrate on an evolutionary model system that exhibits tremendous diversity in dental patterning. My long-term goal is to identify the genes and the developmental programs that integrate differences in tooth shape and tooth number, within and among species of cichlid fish from Lake Malawi, East Africa. The specific goals of this exploratory research are to (i) fine map a region of the cichlid genome that controls tooth shape and (ii) identify patterns of gene expression that generate correlated differences in cichlid tooth and cusp number. Specific Aim 1. Identify the genetic basis of differences in tooth shape. An approximately 3.5 centimorgan interval on cichlid chromosome 5 explains about 40% of the phenotypic variance in an interspecific cross between cichlid species with bicuspid vs. tricuspid teeth. Using fingerprinted BAG libraries in the closely-related tilapia, I will generate a minimum tiling path across this region and sequence overlapping clones at 30-50x coverage, using new high-throughput DMA sequencing technology. Specific Aim 2. Identify the developmental programs that determine differences in tooth number, tooth spacing and cusp number among cichlid species with divergent dental patterns. I will use in situ hybridization to study the role of a number of candidate loci (Bmp4; Fgf4,8; Pax9; Dlx1,2; Shh; Pitx2; Msx; Barx1; Edar; ectodin) in the generation of novelty in cichlid tooth shape and patterning. Accomplishing the exploratory aims outlined above will provide the foundation required to identify genetic changes involved in tooth shape differences among individuals (Aim 1) and will solve the odontogenic code for species with different dental patterning (Aim 2). Knowledge of the genetic and developmental basis of differences in cichlid tooth patterning will lend general insight into vertebrate odontogenesis and will contribute important comparative data for studies in mouse. Results may identify novel therapeutic targets for human dental disorders that warrant further testing in mammalian models. [unreadable] [unreadable] [unreadable]